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Biomedicines
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New Insights and Latest Advances in Corneal and Ocular Surface...
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New Insights and Latest Advances in Corneal and Ocular Surface Diseases

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: 30 November 2025 | Viewed by 2616

Special Issue Editors

Dr. Isabella M. Y. Cheung

E-Mail Website
Guest Editor
Department of Ophthalmology, University of Auckland, Auckland 1023, New Zealand
Interests: healthcare utilisation; keratoconus; healthcare equity
Dr. Akilesh Gokul

E-Mail Website
Guest Editor
Department of Ophthalmology, University of Auckland, Auckland 1023, New Zealand
Interests: keratoconus; corneal crosslinking; anterior segment imaging

Special Issue Information

Dear Colleagues,

In recent years, there have been great gains in diagnosing and managing corneal and ocular surface diseases. Our understanding of such conditions has also progressed significantly, from the infinitesimal molecular aberrations that underpin them to the large-scale epidemiological patterns that occur.

This Special Issue aims to bring together the latest research evidence on these diseases across disciplines. As such, we invite high-quality submissions of original research and review articles on the prevention, diagnosis, and management of corneal and ocular surface diseases and pathobiology. Submissions from across disciplines, including laboratory, clinical and population health-based research, are welcome.

Through a multidisciplinary approach, this Special Issue aims to support a fuller understanding of corneal and ocular surface diseases and ultimately improve patient outcomes through evidence-based practice.

Dr. Isabella M. Y. Cheung
Dr. Akilesh Gokul
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • corneal disease
  • ocular surface disease prevention
  • diagnosis
  • management
  • pathobiology
  • epidemiology
  • health service delivery

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Further information on MDPI's Special Issue policies can be found here.

Published Papers (4 papers)

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Research

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22 pages, 12865 KiB  
Article
Machine Learning-Driven Transcriptome Analysis of Keratoconus for Predictive Biomarker Identification
by Shao-Hsuan Chang, Lung-Kun Yeh, Kuo-Hsuan Hung, Yen-Jung Chiu, Chia-Hsun Hsieh and Chung-Pei Ma
Biomedicines 2025, 13(5), 1032; https://doi.org/10.3390/biomedicines13051032 - 24 Apr 2025
Viewed by 240
Abstract
Background: Keratoconus (KTCN) is a multifactorial disease characterized by progressive corneal degeneration. Recent studies suggest that a gene expression analysis of corneas may uncover potential novel biomarkers involved in corneal matrix remodeling. However, identifying reliable combinations of biomarkers that are linked to disease [...] Read more.
Background: Keratoconus (KTCN) is a multifactorial disease characterized by progressive corneal degeneration. Recent studies suggest that a gene expression analysis of corneas may uncover potential novel biomarkers involved in corneal matrix remodeling. However, identifying reliable combinations of biomarkers that are linked to disease risk or progression remains a significant challenge. Objective: This study employed multiple machine learning algorithms to analyze the transcriptomes of keratoconus patients, identifying feature gene combinations and their functional associations, with the aim of enhancing the understanding of keratoconus pathogenesis. Methods: We analyzed the GSE77938 (PRJNA312169) dataset for differential gene expression (DGE) and performed gene set enrichment analysis (GSEA) using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways to identify enriched pathways in keratoconus (KTCN) versus controls. Machine learning algorithms were then used to analyze the gene sets, with SHapley Additive exPlanations (SHAP) applied to assess the contribution of key feature genes in the model’s predictions. Selected feature genes were further analyzed through Gene Ontology (GO) enrichment to explore their roles in biological processes and cellular functions. Results: Machine learning models, including XGBoost, Random Forest, Logistic Regression, and SVM, identified a set of important feature genes associated with keratoconus, with 15 notable genes appearing across multiple models, such as IL1R1, JUN, CYBB, CXCR4, KRT13, KRT14, S100A8, S100A9, and others. The under-expressed genes in KTCN were involved in the mechanical resistance of the epidermis (KRT14, KRT15) and in inflammation pathways (S100A8/A9, IL1R1, CYBB, JUN, and CXCR4), as compared to controls. The GO analysis highlighted that the S100A8/A9 complex and its associated genes were primarily involved in biological processes related to the cytoskeleton organization, inflammation, and immune response. Furthermore, we expanded our analysis by incorporating additional datasets from PRJNA636666 and PRJNA1184491, thereby offering a broader representation of gene features and increasing the generalizability of our results across diverse cohorts. Conclusions: The differing gene sets identified by XGBoost and SVM may reflect distinct but complementary aspects of keratoconus pathophysiology. Meanwhile, XGBoost captured key immune and chemotactic regulators (e.g., IL1R1, CXCR4), suggesting upstream inflammatory signaling pathways. SVM highlighted structural and epithelial differentiation markers (e.g., KRT14, S100A8/A9), possibly reflecting downstream tissue remodeling and stress responses. Our findings provide a novel research platform for the evaluation of keratoconus using machine learning-based approaches, offering valuable insights into its pathogenesis and potential therapeutic targets. Full article
(This article belongs to the Special Issue New Insights and Latest Advances in Corneal and Ocular Surface Diseases)
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18 pages, 3850 KiB  
Article
RHO-Associated Coiled-Coil-Containing Protein Kinase Inhibitors Significantly Modulate the Epithelial–Mesenchymal Transition Induced by TGF-β2 in the 2-D and 3-D Cultures of Human Corneal Stroma Fibroblasts
by Araya Umetsu, Yosuke Ida, Tatsuya Sato, Megumi Higashide, Nami Nishikiori, Masato Furuhashi, Hiroshi Ohguro and Megumi Watanabe
Biomedicines 2024, 12(12), 2784; https://doi.org/10.3390/biomedicines12122784 - 6 Dec 2024
Viewed by 1050
Abstract
Background/Objectives: The objective of the present study was to examine the unidentified effects that RHO-associated coiled-coil-containing protein kinase 1 and 2 antagonists exert on the transforming growth factor beta2-induced epithelial–mesenchymal transition of the human corneal stroma. Methods: In the presence or absence of [...] Read more.
Background/Objectives: The objective of the present study was to examine the unidentified effects that RHO-associated coiled-coil-containing protein kinase 1 and 2 antagonists exert on the transforming growth factor beta2-induced epithelial–mesenchymal transition of the human corneal stroma. Methods: In the presence or absence of pan-RHO-associated coiled-coil-containing protein kinase inhibitors, ripasudil or Y27632 and RHO-associated coiled-coil-containing protein kinase 2 inhibitor, KD025, we analyzed the following: (1) planar proliferation caused by trans-endothelial electrical resistance and the cellular metabolic characteristics of the two-dimensional cultures of human corneal stroma fibroblasts; (2) the physical properties of a three-dimensional human corneal stroma fibroblasts spheroid; and (3) the gene expressions and their regulators in the extracellular matrix, along with the tissue inhibitors of metalloproteinases and matrix metalloproteinases and the endoplasmic reticulum stress-related factors of the two-dimensional and three-dimensional cultures in human corneal stroma fibroblasts. Results: Exposure to 5 nM of the transforming growth factor beta2 markedly increased the trans-endothelial electrical resistance values as well as the metabolic function in two-dimensional cultures of human corneal stroma fibroblasts. With an increase in stiffening, this exposure also reduced the size of three-dimensional human corneal stroma fibroblast spheroids, which are typical cellular phenotypes of the epithelial–mesenchymal transition. Both pan-RHO-associated coiled-coil-containing protein kinase inhibitors and RHO-associated coiled-coil-containing protein kinase 2 inhibitors substantially modulated these transforming growth factor beta2-induced effects, albeit in a different manner. Gene expression analysis supported such biological alterations via either with transforming growth factor beta2 alone or with the RHO-associated coiled-coil-containing protein kinase inhibitors variants with the noted exception being the transforming growth factor beta2-induced effects toward the three-dimensional human corneal stroma fibroblast spheroid. Conclusions: The findings presented herein suggest the following: (1) the epithelial–mesenchymal transition could be spontaneously evoked in the three-dimensional human corneal stroma fibroblast spheroid, and, therefore, the epithelial–mesenchymal transition induced by transforming growth factor beta2 could differ between two-dimensional and three-dimensional cultured HCSF cells; and (2) the inhibition of ROCK1 and 2 significantly modulates the transforming growth factor beta2-induced an epithelial–mesenchymal transition in both two-dimensionally and three-dimensionally cultured human corneal stroma fibroblasts, albeit in a different manner. Full article
(This article belongs to the Special Issue New Insights and Latest Advances in Corneal and Ocular Surface Diseases)
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Review

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16 pages, 1221 KiB  
Review
Advancing Bilateral Limbal Deficiency Surgery: A Comprehensive Review of Innovations with Mucosal Cells
by Zahra Bibak-Bejandi, Mohammad Soleimani, Zohreh Arabpour, Emine Esra Karaca, Elmira Jalilian, Hassan Asadigandomani, Reyhaneh Bibak-Bejandi and Ali R. D’jalilian
Biomedicines 2025, 13(3), 630; https://doi.org/10.3390/biomedicines13030630 - 5 Mar 2025
Viewed by 595
Abstract
Besides alternative surgical methods for bilateral limbal deficiency, such as KLAL (keratolimbal allograft), living-related conjunctival limbal allograft (LR-CLAL), and keratoprosthesis, regenerative medicine often necessitates the use of alternative sources of limbal cells in cases where access to fellow eye source cells is limited. [...] Read more.
Besides alternative surgical methods for bilateral limbal deficiency, such as KLAL (keratolimbal allograft), living-related conjunctival limbal allograft (LR-CLAL), and keratoprosthesis, regenerative medicine often necessitates the use of alternative sources of limbal cells in cases where access to fellow eye source cells is limited. Mucosal cells are most commonly used to restore limbal tissue in such scenarios. Current techniques involving mucosal cells include cultivated oral mucosal transplantation (COMT), oral mucosal graft transplantation (OMGT), and simple oral mucosal transplantation (SOMT). COMT requires suspension of cells and a culturing process that is time-consuming and cost-prohibitive. In contrast, OMGT requires solely a strip of mucosal graft for transplanting into the deficient eye. The most recently developed practice, SOMT, in which chopped biopsy tissue is transplanted into the deficient area, compensates for problems associated with both COMT and OMGT, making the process of addressing bilateral limbal deficiency easy, time-saving, and affordable. Although some undesirable outcomes, such as angiogenesis, can occur post-transplantation, and the ultimate goal of differentiation into limbal epithelial stem cells may not be achieved, mucosal cell sources can be a good alternative for stabilizing the ocular surface. Some studies emphasize that co-culturing limbal niches in mucosal cell cultures can enhance differentiation capability. This concept highlights the importance of the limbal environment in the differentiation process. In this review, we demonstrate the ongoing changes in surgical technique trends and how they have made mucosal cell transplantation easier and more effective for limbal regeneration. Full article
(This article belongs to the Special Issue New Insights and Latest Advances in Corneal and Ocular Surface Diseases)
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Other

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11 pages, 1087 KiB  
Opinion
Ocular Surface Microbiota and Corneal Transplant Outcome: Is There a Link?
by Michele Potenza, Antonio Moramarco, Annalisa Astolfi, Carmen Ciavarella, Luigi Fontana and Piera Versura
Biomedicines 2025, 13(4), 972; https://doi.org/10.3390/biomedicines13040972 - 16 Apr 2025
Viewed by 216
Abstract
Recent research has highlighted the critical role of microbiota in organ transplant outcomes, particularly in the gut. However, the impact of ocular surface microbiota (OSM) on corneal transplantation remains largely unexplored. This piece examines the potential connection between OSM imbalances and corneal graftoutcomes, [...] Read more.
Recent research has highlighted the critical role of microbiota in organ transplant outcomes, particularly in the gut. However, the impact of ocular surface microbiota (OSM) on corneal transplantation remains largely unexplored. This piece examines the potential connection between OSM imbalances and corneal graftoutcomes, suggesting that microbial shifts could influence immune responses and transplant success. The OSM, though characterized by low microbial density, plays a critical role in local immune modulation and ocular surface homeostasis. Dysbiosis in this microbiota may compromise the immune privilege of the cornea, potentially increasing the risk of graft rejection. Looking at gut microbiota studies, where dysbiosis has been linked to graft failure, it is reasonable to hypothesize that similar mechanisms might be at play on the ocular surface. Disruptions in cornea’s immune tolerance pathways, such as anterior chamber-associated immune deviation (ACAID), may lead to pro-inflammatory responses that threaten graft survival. In addition, ocular surface diseases such as dry eye disease, microbial keratitis, and allergic conjunctivitis, already associated with OSM dysbiosis, may further exacerbate post-transplant complications. Despite the lack of direct studies linking OSM to corneal transplant outcomes, this opinion piece highlights the necessity for future research. Standardizing microbiota analysis methodologies and exploring therapeutic interventions, such as ocular probiotics, could open new roads for improving corneal transplant success and patient prognosis. Full article
(This article belongs to the Special Issue New Insights and Latest Advances in Corneal and Ocular Surface Diseases)
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